let-7b靶向肺癌细胞提高放疗杀伤作用及机制的实验研究

放疗抵抗是肺癌治疗失败的主因，目前基于抑癌miRNA的研究是解决问题的重要方向。let-7是其中最重要的一个抑癌miRNA，但单独应用let-7靶向癌细胞提高放疗敏感性的作用不明显。我们前期发现，let-7在肺癌细胞（LCC）中异常表达，CDKN1A和CDKN1B为其靶基因，let-7表达增加可消除细胞G1/S阻滞，对S期特异性化疗药CPT-11敏感。在此基础上，本项目设计了一种新型的双源纳米粒子let-7b CPT-11 co-loaded HA-chitosan NP (CNP)，将let-7b与CPT-11包装入纳米粒子，通过透明质酸靶向LCC，let-7b消除细胞G1/S阻滞，进入S期细胞比例增多，CPT-11联合放疗提高放疗的杀伤作用，并研究DNA损伤修复基因在其中的作用，为克服肺癌放疗抵抗提供新策略。

Resistance to radiation is the main cause of treatment failure in lung cancer. Research on tumor suppressor miRNA is an important means to solve this problem. Let-7 is one of pivotal tumor suppressor microRNAs, however, the effect of let-7 targeted lung cancer cell (LCC) alone to improve the radiotherapy sensitivity is not significant. Our previous research revealed that let-7 is abnormally expressed in LCC. CDKN1A and CDKN1B are the targets of let-7b. Overexpressed let-7 will eliminate G1/S block, thus induce the sensitivity of LCC to S phase-specific chemotherapeutic agent-CPT-11. Thus, we developed a novel dual nanocarrier system let-7b CPT-11 co-loaded HA-chitosan nanoparticle (CNP). HA, conjugated with the NP, can combined with CD44 on the surface of LCC, thus targeted LCC to restore its let-7b level. Let-7 will eliminate G1/S block, increase the proportion of S phase LCC and improve the killing effect of radiotherapy to LCC by CNP. We will explore the role of DNA damage repair genes. Our research will provide new therapeutic strategies for overcoming the radioresistance of lung cancer.